Neonatal infections are traumatic manifestations of herpes simplex virus (HSV) due to exposure to HSV- 1 or HSV-2 either during parturition or the early postnatal period. Neonates are particularly susceptible with approximately 50% of infected newborns developing disseminated disease or encephalitis. Without treatment, mortality is high and surviving infants with central nervous system (CNS) involvement suffer long-term neurodevelopmental disabilities, incurring significant economic burden. Acyclovir (ACV) and its derivatives are the current standard treatment, but initiation of such therapy requires a high degree of clinical suspicion. Even aggressive ACV treatment of neonates with generalized infection leaves an estimated 70% with neurological sequelae. The global incidence of neonatal HSV (nHSV) is estimated to be 1.03 per 10,000 live births, with ~15,000 cases of nHSV annually, and 1,500 of these in the US. It is imperative, therefore, that new options be considered for prevention and treatment of HSV infection in this most vulnerable of populations. nHSV transmission patterns are counterintuitive. HSV vertical transmission risk is low ( ?1% of cases) from mothers with long-standing pre-existing genital infections, even with proven recurrence during birth. ?85% of cases occur when there is a maternal primary infections during birth, and 10-15% of cases follow postnatal exposure. This risk pattern is consistent with the hypothesis that protection is conferred through transfer of maternal antibodies. These antibodies cross the placenta and supplement the underdeveloped fetal and neonatal immune system to protect against congenital infections. Our previous work demonstrated that maternal antibodies access neural tissues of the fetus with surprising efficiency and is sufficient to prevent nHSV in mice. Preliminary data now demonstrate a novel mouse model system whereby we can model not only mortality and viral burden, but also behavioral pathologies that are frequent and lifelong in humans following nHSV. We present preliminary data to show that administration of HSV-specific IgG to dams prevents behavioral morbidity and mortality in their offspring when they are challenged with HSV immediately after birth. These data have been generated using pilot funding from Dartmouth College and this R21 is key to continuation of this research. Our overarching goal is to explore use of a therapeutic monoclonal antibody (mAb) (E317) to prevent nHSV. We will administer IgG either to the dam, or to the offspring pre- or post-exposure, alone, or in combination with ACV. E317 has the advantage of being reactive against gD of HSV-1 and HSV-2 and is strongly neutralizing to both. If successful, these translational studies will demonstrate whether maternal or postnatal administration of an HSV-neutralizing mAb can prevent nHSV. These studies are relevant not only to HSV but also to other neurotropic neonatal pathogens (e.g. Zika and CMV). Overall, this work will provide key data relevant to two problems of high clinical significance?development of maternal interventions targeted to improve neonatal health outcomes, and delivery of therapeutic Abs into the nervous system for treatment of neurological disorders.